Collagen, the major extracellular matrix (ECM) component of connective tissues, has received a great deal of attention as a candidate material for use as an implantable or injectable drug delivery vehicle, primarily because of its biocompatibility, low immunogenicity and biodegradability. Extracellular matrices are known to provide scaffolding for cells, while organizing the cells three-dimensionally and providing essential information to regulate cell behavior. As such, the field of tissue engineering strives to mimic both the form and function of these scaffolds to create compositions for optimal tissue repair and replacement. Collagen, and in particular type I collagen, may be used in the field of tissue engineering due to its high availability in the body, conservation across tissues and species, biodegradability and biocompatibility. In fact, not only is collagen the most abundant molecule of the ECM, it is responsible for the majority of the structural and mechanical properties of several tissues. The in vivo form of collagen is a triple-helix center region that is capped at both ends by randomly organized telopeptides. These collagen molecules are found within the ECM assembled as branched collagen-fibril networks that contain natural molecular cross-links.
In spite of numerous advantages and wide research on collagen as a natural biomaterial, its use as a vehicle for controlling local active agent release has been limited. Furthermore, its application as a tissue graft that induces appropriate tissue regeneration while at the same time achieving predictable localized delivery of specified agents has not been achieved to date. In fact, only a few collagen-based active agent delivery formulations have made it into clinical trials. Existing formulations can be categorized as either non-dissociated fibrillar collagens or solubilized collagens. These formulations have a number of shortcomings, including poorly defined molecular composition, low mechanical integrity, rapid biodegradation and limited control over drug release profiles.
Non-dissociated fibrillar collagens are formulations that contain decellularized collagen extracellular matrix (ECM) particulate matter, which is mechanically homogenized, acid-swollen, and finally lyophilized to form sponge that may or may not be cross-linked. Soluble collagens, by contrast, are obtained from pepsin or acid solubilization of mammalian tissues to form viscous collagen solutions, which are then lyophilized and formulated as a cross-linked or non-cross-linked sponge or injectable viscous gel. As stated above, previously-described collagen-based active agent delivery platforms have many limitations, including poorly defined molecular compositions, low mechanical integrity and stability, rapid proteolytic degradation rapid proteolytic degradation and limited design control. While exogenous crosslinking, including chemical and physical means, is routinely used to improve mechanical and handling properties as well as increase persistence upon implantation, such processing is associated with deleterious tissue responses and loss of biological activity.
The marginal success of these present day collagen-based drug delivery formulations can be traced to these major limitations. Moreover, these conventional formulations exhibit amorphous microstructures, with unsatisfactory control of material properties, including pore size and proteolytic degradability. Cursory control of these parameters is often achieved through modulation of lyophilization conditions and/or exogenous chemical and physical crosslinking. Materials formed without cross-linking represent viscous gels. They are characterized as mechanically unstable, too soft to handle, and unable to resist cell-induced contractions, thus failing to support cell ingrowth and migration required for tissue regeneration. On the other hand, exogenous crosslinking has been shown to have detrimental effects on cells and tissues, such as cytotoxicity or tissue calcification and partial denaturation of collagen itself. Aldehyde based cross-linking may lead to aldehyde residues in the final product and may influence the biocompatibility of the collagen. Moreover, de-hydrothermal cross-linking has natural limitations and does not lead to materials with sufficiently improved properties.
Accordingly, there is a need for further advancements in the design and development of local therapeutic delivery systems and integrated tissue regeneration. As will be explained in detail herein, the present disclosure addresses this need and also provides associated compositions, devices and methods that address deficiencies in the existing art.